Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present invention relates to a new process for preparing thiazolidinedione compounds which includes the step of reduction of a thiazolidinedione precursor. More particularly, the present invention relates to preparation of thiazolidinedione compounds having antihyperglycemic properties.
• Thiazolidinedione antihyperglycemic compounds represent a class of pharmaceuticals which act principally by decreasing insulin resistance in patients suffering from non-insulin-dependent diabetes. Therefore thiazolidinedione antihyperglycemic compounds are used typically as active substances in various pharmaceutical preparations for the treatment of type II diabetes and other disorders related to insulin resistance.
• Pioglitazone (5-[[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, according to Merck Index/13th Edition/Monograph number 7533, CAS Registry number: 111025-46-8) has the formula I
• Pioglitazone is currently marketed as pioglitazone hydrochloride (5-[[4-[2-(5-ethyl-2- pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione monohydrochloride).
• Rosiglitazone (5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, according to Merck Index/13th Edition/Monograph number 8346, CAS Registry number: 122320-73-4), and troglitazone (5-[[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-l- benz ⁇ pyran-2-yl)methoxy]phenyl]methyl]-2,4-thiazolidinedione, according to Merck Index/13th Edition/Monograph number 9838, CAS Registry number: 97322-87-7) are other thiazolidinedione antihyperglycemic compounds useful for treating type II diabetes and other disorders related to insulin resistance.
• Processes for making pioglitazone, rosiglitazone and troglitazone may proceed via a thiazolidinedione precursor having an exocyclic carbon-carbon double bond at the 5-position of the thiazolidinedione moiety.
• the carbon-carbon double bond is e.g. hydrogenated to a carbon-carbon single bond to form the thiazolidinedione antihyperglycemic compound; inter alia, catalytic hydrogenation over a supported catalyst may be applied as known.
• a method for making pioglitazone for example, is disclosed in US patent 5,952,509.
• Most known processes comprise demanding methods involving e.g. the above mentioned catalysts, or e.g. the use of cobalt ions.
• These methods apply agents which are either relatively expensive and/or ecologically critical regarding their handling, and which are often combined with the use of hydrogen under high pressures, the handling of which requires costly safety measures and special reaction apparatus.
• the present inventors have found that reduction of the thiazolidinedione precursor to form the corresponding thiazolidinedione antihyperglycemic compound may be effected in a simple and cost-effective way by avoiding ether solvents, which makes it more attractive from an industrial and ecological point of view.
• the present invention provides a process for reducing an exocyclic double bond at the 5-position of a thiazolidinedione moiety of a thiazolidinedione precursor comprising the steps of: a) preparing a solution or suspension of the thiazolidinedione precursor in a non-ether solvent medium with a base, and b) combining the solution or suspension with a dithionite source.
• the dithionite source may comprise sodium-, lithium-, potassium-, calcium-, magnesium-, a tetraalkylammonium- or a guanidinium-dithionite.
• the dithionite source acts as a reducing agent.
• the solution or suspension of the thiazolidinedione precursor in the solvent medium with the base may be combined with the dithionite source at elevated temperatures.
• the process of the present invention may further comprise isolation of the reduced thiazolidinedione precursor.
• the present invention provides a process for preparing a thiazolidinedione antihyperglycemic compound comprising reduction of the exocyclic double bond at the 5-position of a thiazolidinedione moiety of a thiazolidinedione precursor, especially a thiazolidinedione precursor of pioglitazone, rosiglitazone, or troglitazone, which process comprises the steps of: a) preparing a solution or suspension of the thiazolidinedione precursor in a non- ether solvent medium with a base, and heating the solution or suspension to a temperature of about 40°C to 100°C, b) combining the solution or suspension with a dithionite source selected from the group of sodium-, lithium-, potassium-, calcium-, magnesium-, a tetraalkylammonium- or a guanidinium-dithionite, to provide a reaction mixture, c) maintaining the reaction mixture at a temperature of about
• the reaction mixture may be cooled to about 0°C to 30°C before isolation of the thiazolidinedione antihyperglycemic compound.
• non-ether solvent to mean a solvent which is free of, or substantially free of, any -C-O-C- linkage.
• Any ether solvent present i.e. a solvent having a -C-O-C- linkage, is present in trace amounts only, e.g. up to about 5 wt-%, e.g. 0.1 to 3 wt- %, for example 2, 1.5, 1 or 0.5 wt-% or less, based on the total weight of the solvent medium.
• the present invention provides therefore a process for preparing pioglitazone including the step of reducing the pioglitazone precursor 5-[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methenyl- 2,4-thiazolidinedione comprising the above mentioned steps and isolating pioglitazone free base.
• the present invention provides a process for preparing rosiglitazone including the step of reducing the rosiglitazone precursor 5-[4-[2-(methyl-2-pyridinylamino) ethoxy]phenyl]methenyl-2,4-thiazolidinedione comprising the above mentioned steps and isolating rosiglitazone free base.
• the present invention provides a process for preparing troglitazone including the step of reducing the troglitazone precursor 5-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8- tetramethyl-2H-l-benzopyran-2-yl)methoxy]phenyl]methenyl-2,4-thiazolidinedione comprising the above mentioned steps and isolating troglitazone free base.
• the selective reduction process as herein described may take place in the presence of a phase-transfer catalyst.
• the process as described herein may lead to the corresponding thiazolidinedione antihyperglycemic compound in the form of the free base, which is obtained, e.g. in crystalline form, in a high yield and with high purity.
• the free base of the thiazolidinedione antihyperglycemic compound may be further purified and/or converted to a derivative, e.g. to a pharmaceutically acceptable salt, e.g. to the hydrochloride in the case of pioglitazone, or e.g. to the maleate in the case of rosiglitazone, by known methods.
• a pharmaceutically acceptable salt e.g. to the hydrochloride in the case of pioglitazone, or e.g. to the maleate in the case of rosiglitazone, by known methods.
• a "thiazolidinedione precursor" as used herein, is understood to mean a compound which is an intermediate in a process for making a thiazolidinedione antihyperglycemic compound, such as the process disclosed in US patent 5,952,509, incorporated herein by reference, and that has a thiazolidinedione moiety.
• a preferred thiazolidinedione precursor is a precursor which differs structurally from the corresponding thiazolidinedione antihyperglycemic compound itself in that the preferred thiazolidinedione precursor has an exocyclic double bond at the 5-position of the thiazolidinedione moiety.
• a preferred thiazolidinedione precursor may have protected functional groups e.g. protected hydroxyl groups.
• thiazolidinedione precursor for pioglitazone is an example of a preferred thiazolidinedione precursor for pioglitazone, which may be prepared according to the method of Saito et al. disclosed in US patent 5,952,509, or in published European patent application EP 0 816 340.
• the compound 5-[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methenyl-2,4-thiazolidine- dione is an example of a preferred thiazolidinedione precursor for rosiglitazone, and is disclosed, for example, in US patent 5,002,953.
• the compound 5-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-l-benzopyran-2-yl) methoxy]phenyl]methenyl-2,4-thiazolidinedione, or hydroxy group protected derivatives thereof, are examples of preferred thiazolidinedione precursors for troglitazone, as disclosed e.g. in J. Crossy et al., Bioorganic and Medicinal Chemistry Letters 9, pp. 3439, 1999.
• the process according to the present invention is carried out as follows:
• a solution or suspension is prepared by combining a thiazolidinedione precursor, e.g. a preferred thiazolidinedione precursor of pioglitazone, e.g. 5-[4-[2-(5-ethyl-2-pyridinyl)ethoxy] phenyl]methenyl-2,4-thiazolidinedione, with 5 to 100 volumes of a suitable solvent medium, and with 1 to 30 molar equivalents, preferably 5 to 15 molar equivalents, of a suitable base.
• Molar equivalents mean "as compared to the thiazolidinedione precursor used".
• Suitable bases comprise an alkaline or alkaline earth carbonate, e.g. sodium carbonate, potassium carbonate or lithium carbonate, an alkaline hydrogen carbonate, e.g. sodium bicarbonate, an organic secondary or tertiary amine, e.g. piperidine, or an amidine, e.g. DBU (i.e. l,8-diazabicyclo[5.4.0]undec-7-en).
• Preferred bases comprise sodium carbonate or potassium carbonate.
• a suitable solvent medium may comprise an aqueous medium, which includes water or a mixture of water with one or more non-ether organic solvents, wherein the ratio of water to organic solvent/s may be 10 : 1 to 1 : 10 (v/v).
• the solvent medium may comprise a solvent and a co-solvent.
• Suitable organic solvents include alcohols, for example methanol, ethanol or isopropanol; alkyl esters such as ethyl acetate; aromatic hydrocarbons, e.g. toluene or xylene; halogenated hydrocarbons, e.g. methylene chloride; amides, e.g. N,N-dimethylformamide or N,N- dimethylacetamide, or a urea, e.g. urea or a tetra-alkylurea such as tetra-methylurea.
• a preferred solvent medium is N,N-dimethylformarnide and water.
• the use of the DMF/water solvent medium serves to provide that the unsaturated precursor is present typically in amounts below 0.1 wt-% in the final product, reproducibly. This is especially important since the separation of the unsaturated precursor from the reduced product is not possible as a practical matter, economically, through known purification methods. It has been observed that in other solvent mixtures, the poor solubility of the precursor often causes its undesired and unexpected precipitation which makes the reduction non-reproducible.
• the ratio of DMF:water may range from 1:1 to 1:10, e.g. 1:2 (v/v) to 1:4 (v/v).
• the resulting mixture of the thiazolidinedione precursor, the base and the solvent medium is subsequently heated to an elevated temperature of about 40° to 100°C, preferably of about 50°C to 90°C , most preferably of about 60°C to 80°C.
• 1 to 30 molar equivalents, preferably 5 to 20 molar equivalents (as compared to the thiazolidinedione precursor used), of the dithionite source may be added either in portions or, e.g. drop-wise, as a solution, preferably in water, over a period of a few minutes up to 2 hours, preferably over a period of about 30 min to 1 hour.
• the resulting reaction mixture is subsequently maintained at the above mentioned elevated temperature during the reduction process, which lasts for about 1 to 10 hours depending on the temperature employed, e.g. for about 1 to 3 hours if the temperature is maintained at about 80°C.
• Suitable dithionite sources comprise sodium-, lithium-, potassium-, calcium-, magnesium-, aluminium-dithionite, or a tetraalkylammonium-dithionite, e.g. a tetraethylammonium- dithionite, or a guanidinium-dithionite.
• a preferred dithionite source is sodium dithionite.
• the reaction mixture may be cooled to induce or enhance crystallization.
• the cooling procedure may be effected stepwise, e.g. in a first step to a temperature of about 50°C, and subsequently to about 30°C to 0°C , preferably to about 10 °C.
• the cooling procedure may be performed so as to provide a substantially constant rate of temperature decrease.
• the pH-value may be adjusted to about 2 to 8, preferably to about 5 to 6, most preferably to about 6, by adding, e.g. acetic acid, e.g. 50 to 60% (v/v) aqueous acetic acid.
• the precipitate formed may subsequently be collected by conventional methods such as filtration, washing and vacuum drying.
• the resulting free base of the thiazolidinedione antihyperglycemic compound e.g. pioglitazone free base
• the resulting pioglitazone free base may be converted directly to pioglitazone hydrochloride.
• phase-transfer catalyst may comprise e.g. a tetrabutylammonium halide, a tetraethylammonium halide or a benzyl tributylammonium halide.
• a phase-transfer catalyst may comprise e.g. a tetrabutylammonium halide, a tetraethylammonium halide or a benzyl tributylammonium halide.
• Halide as used herein is understood to mean a bromide, chloride or fluoride of the corresponding compound.
• the reduction process as described for the present invention is highly selective, which means that side-products may be formed in small amounts only and which may typically be removed during the subsequent processing of the base of the thiazolidinedione antihyperglycemic compound to a purified form of said base and/or to a derivative thereof, e.g. in the case of pioglitazone, a hydrochloride form.
• the free base of the thiazolidinedione antihyperglycemic compound may be further purified by known methods, e.g. by tituration with alcoholic solvents, or by standard crystallization procedures, e.g. using organic solvents, e.g. dioxane or N,N-dimethylformamide, as crystallisation solvents.
• pioglitazone free base as obtained by the process herein described may be processed to the hydrochloride or other pharmaceutically acceptable salts by known methods, optionally after a purification step as described above.
• pioglitazone free base as obtained by the reduction process of the invention is converted to the hydrochloride form by dissolving the crystals of the free base in a solvent, e.g. in an alcohol, e.g. ethanol, e.g. in 1 to 10 volumes, preferably 1 to 6 volumes, of ethanol, and a) by adding hydrochloric acid, e.g. aqueous hydrochloric acid, e.g. 1 tolO volumes, preferably 1 to 6 volumes, of 2 N HCl, or b) by adding an ethanol containing hydrochloric acid, e.g. ethanolic hydrochloric acid, e.g.
• pioglitazone HCl obtained as described above may be performed by known methods, e.g. by recrystallization from a solvent selected from the group of N,N- dimethylformamide, dimethyl acetamide, acetic acid, methanol, ethylene glycol, isopropyl alcohol and t-butyl alcohol.
• pioglitazone HCl may be recrystallized from ethanol as disclosed by Sodha et al., Arzneim.-Forschung/Drug Res. 40 (I), No. 1, 1990, pp. 37.
• Pioglitazone HCl obtained by the above described conversion of the pioglitazone free base as obtained by the present invention corresponds to the known anhydrous crystalline form I.
• Form I pioglitazone HCl may be used for the conversion to known crystalline pioglitazone form II employing known methods.
• rosiglitazone free base as obtained by the process herein described may be processed to the maleate or other pharmaceutically acceptable salt form by known methods, e.g. as described in US patent 5,741,803, optionally after a purification step as described above for pioglitazone free base.
• rosiglitazone free base as obtained by the process of the invention may be converted to the maleate form by a) dissolving the crystals of the free base in a solvent, e.g. in acetone , e.g. in 10 to 14 volumes, preferably 10 to 11 volumes, of acetone, and b) adding maleic acid dissolved in e.g. 10 to 15 volumes acetone, c) heating the reaction mixture thus obtained to around 50-60°C and by subsequently crystallizing the maleate salt from the resulting solution by gradual cooling in order to obtain pure rosiglitazone maleate e.g. with HPLC-purity of > 98%.
• rosiglitazone free base as obtained by the process of the invention may be converted to the maleate form by a) dissolving or suspending crystals of the free base and maleic acid in a solvent, e.g. ethanol, b) heating the suspension at around boiling temperature, c) optionally treating the mixture with charcoal or diatomaceous earth, d) filtering, e) cooling the solution and crystallizing the maleate, and optionally f) isolation and drying of rosiglitazone maleate.
• a solvent e.g. ethanol
• rosiglitazone maleate obtained as described above may be performed by known methods, e.g. by recrystallization from a solvent selected from the group of N,N-dimethylformamide, dimethyl acetamide, acetic acid, methanol, ethylene glycol, isopropyl alcohol and t-butyl alcohol.
• the free base of the thiazolidinedione antihyperglycemic compounds obtained according to the invention, and the derivatives thereof, e.g. pioglitazone HCl or rosiglitazone maleate, may be used in the manufacture of pharmaceutical compositions which are useful for the treatment of patients suffering from diabetes type II or diseases in which insulin resistance is the underlying pathophysiological mechanism.
• Further aspects of the invention include the use of pioglitazone free base as obtained using the processes described herein for conversion to the hydrochloride or other pharmaceutically acceptable salt form of pioglitazone;
• pioglitazone as free base or as hydrochloride as obtained using the processes described herein for the manufacture of a medicament for the administration to a mammal in need thereof;
• rosiglitazone free base as obtained using the processes described herein for conversion to the maleate or other pharmaceutically acceptable salt form of rosiglitazone; and the use of a dithionite source in the presence of a non-ether solvent medium to reduce selectively an exocyclic double bond at the 5-position of a thiazolidinedione moiety of a thiazolidinedione precursor to obtain the corresponding thiazolidinedione compound.
• the processes of this invention are carried out at ambient atmospheric pressure.
• Example 1 The conditions and procedure are followed as for Example 1, but using 15.6 g potassium carbonate instead of 19.5 g of sodium carbonate, and 150 ml dioxane instead of 75 ml, and 14.7 g of sodium dithionite in 75 ml water instead of 28 g of sodium dithionite in 150 ml water.
• Example 2 The conditions and procedure of Example 2 are followed, but using a 1 : 2 mixture of ethyl acetate and water, i.e. a mixture of 75 ml ethyl acetate and 150 ml water, instead of a mixture of dioxane and water, as solvent medium.
• a 1 : 2 mixture of ethyl acetate and water i.e. a mixture of 75 ml ethyl acetate and 150 ml water, instead of a mixture of dioxane and water, as solvent medium.
• Example 2 The conditions and procedure of Example 2 are followed, but using a 1 : 6 mixture of N,N- dimethylformamide and water, i.e. a mixture of 25 ml of N,N-dimethylformamide and 150 ml water, instead of a mixture of dioxane and water, as solvent medium.
• a 1 : 6 mixture of N,N- dimethylformamide and water i.e. a mixture of 25 ml of N,N-dimethylformamide and 150 ml water, instead of a mixture of dioxane and water, as solvent medium.
• Example 2 The conditions and procedure of Example 2 are followed, but using 225 ml water instead of a mixture of dioxane and water, as solvent medium.
• Example 2 The conditions and procedure are followed as for Example 1, but using a 1 : 3 mixture of toluene and water, i.e. a mixture of 75 ml toluene and 225 ml water, instead of a mixture of dioxane and water, as solvent medium, and adding 0.5 g tetrabutyl ammonium bromide into the round-bottomed flask before heating the resulting mixture.
• a 1 : 3 mixture of toluene and water i.e. a mixture of 75 ml toluene and 225 ml water, instead of a mixture of dioxane and water, as solvent medium, and adding 0.5 g tetrabutyl ammonium bromide into the round-bottomed flask before heating the resulting mixture.
• Example 8 The conditions and procedure of Example 8 are followed, but using a 1 : 1 mixture of ethanol and 2 N HCl, i.e. a mixture of 18 ml ethanol and 18 ml 2 N HCl, instead of a mixture of ethanol and ethanolic hydrochloric acid.
• Example 11 Preparation of pure 5-[4-[N-(2- pyridinyl)-N- methyl) ethoxy]phenyl]methenyl-2.4- thiazolidinedione (rosiglitazone unsaturated base)
• 2-chloropyridine 850 ml N- methyl aminoethanol is added at room temperature and the reaction mixture is heated to about 120°C under agitation and heated for about 24 hours in round bottom flask. The progress of the reaction is monitored by TLC. After completion of the reaction, the excess of N- methyl aminoethanol is then distilled out under high vacuo at about 80°C.
• reaction mixture is cooled to about room temperature and then quenched with 2.54 Lt water and stirred for about 30 minutes. It is then extracted with 2*508 ml methylene chloride and then organic layer is washed with 3* 1.2 Lt water, dried over 25 g sodium sulphate and then concentrated under vacuo at about 45°C to get 182 g pyridyl benzaldehyde as an oil.
• the suck dried material is then purified by stirring at about room temperature using 1000 ml dimethyl formamide for about 1 hour.
• the suspension is then cooled to about 0-5°C and stirred at this temperature for about 2-3 hours and then filtered, washed with methanol and then vacuum dried at about 70°C for approximately 10 hours to get pure 160.8 g of 5-[4-[N- (2- pyridinyl)-N- methyl) ethoxy]phenyl]methenyl-2,4-thiazolidinedione.
• Pioglitazone Reference Example 1 Preparation of 5-[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methenyl-2.4-thiazolidinedione from 5-Ethyl-2-pyridine ethanol 10 g of 5-ethyl-2-pyridine ethanol, 10.2 ml triethylamine and 75 ml toluene are added to the round bottom assembly at ambient temperature. Thereafter 6.16 ml methane sulfonyl chloride are added via dropping funnel in 1 hour. The reaction mixture is stirred at ambient temperature for 1 hour and then washed with water.
• the resulting mixture is then heated to about 80 C C under agitation. At about 80°C a solution of 29.5 g sodium dithionite in 150 ml water is added drop-wise within about 60 minutes. 150 ml tetrahydrofuran are added, the reaction mixture stirred at about 65°C for approximately 3 hours, cooled to about 10°C and stirred at about 10°C for about 30 minutes. The precipitate is filtered, washed with 100 ml water, and the title compound is collected after drying in a vacuum oven for about 8 hours at approximately 65 °C.
• the resulting mixture is then heated to about 80°C under agitation. At about 80°C a solution of 29.5 g sodium dithionite in 100 ml water is added drop- wise within about 60 minutes. 150 ml 1,4 dioxane are added, the reaction mixture stirred at about 80°C for approximately 3 hours, cooled to about 10°C and then stirred at about 10°C for about 30 minutes. The precipitate is filtered, washed with 100 ml water, and the title compound is collected after drying in a vacuum oven for about 8 hours at approximately 65°C.
• Table B indicates HPLC analyses for pioglitazone (PG-90) and the precursor 5-[4-[2-(5-ethyl-2-pyridinyl)ethoxy]phenyl]methenyl-2-4,thiazolidinedione abbreviated "PG-60".
• the amounts of unreacted precursor are very low for DMF/water solvent media in comparison with an ether/water solvent medium.
• the reaction conditions used are as used above, or analogous to the above reaction parameters.
• the HPLC results are area-%.
• Table B Comparative results for co-solvents used for reduction using sodium dithionite with water as solvent
• thiazolidinedione antihyperglycemic compounds e.g. pioglitazone, rosiglitazone, or troglitazone, e.g. in the form of their free bases
• reducing selectively their respective preferred thiazolidinedione precursors by using a dithionite source in the absence of an ether as described in the present invention involves a novel reduction process which is attractive both from economic and ecological standpoints.
• the reduction process of the invention displays the same or similar selectivity related to the reduction of the thiazolidinedione precursors, and leads to the same or similar high yields and high purity of the thiazolidinedione antihyperglycemic compounds, e.g. of the pioglitazone free base and HCl, as hitherto known processes.
• the process of the present invention offers, however, the advantages of using reaction agents which are readily commercially available, cheap, ecologically "unrisky” and which avoid potentially dangerous handling.
• reaction of this invention using sodium dithionite with an aqueous DMF solvent medium is particularly attractive. Conversion of precursor is substantially more complete than with hitherto known processes.

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